Ventricular remodeling after myocardial infarction (Ml) is a pathologic response characterized by progressive left ventricular dilatation and at the cellular level by myocyte hypertrophy, fibroblast proliferation and collagen deposition. Data from both in vivo and in vitro studies show that angiotensin II (A-Il) plays an important role in these processes, but the molecular mechanisms involved are not well understood. Our preliminary data in a murine model support the hypothesis that activation of the AT1 receptor primarily mediates myocyte hypertrophy following MI, while fibroblast proliferation and collagen deposition both involve a combination of AT1- and non-AT1 receptor Activation. To test this hypothesis, we have developed a mouse model of MI and now propose to apply this novel model to normal mice and transgenic mice in which the AT1 receptor gene has been disrupted. The three specific aims of this proposal include: Specific Aim l: To characterize the role of angiotensin II and the AT1 receptor in post- Ml ventricular remodeling in normal mice, defining the time course of cellular and gene expression changes characteristic of remodeling, as well as the effect of (a) ACE-inhibition and (b) AT 1-receptor blockade on these events; Specific Aim 2: To study the process of post-Nil ventricular remodeling in transgenic mice with a disruption of the AT1 receptor, and the effects of ACE-inhibition and AT1 receptor blockade on post-Ml ventricular remodeling in these mice; and Specific Aim 3: To explore potential non-AT1 mediated pathways in post-MI remodeling by studying AT1 receptor-deficient mice treated with an AT2 receptor antagonist. The mouse model of myocardial infarction provides unique opportunities to investigate the role of specific gene products in ventricular remodeling following Ml. These studies will help define the role of A-II and the AT1 and AT2 receptors in the cellular and molecular events that underlie post-Ml ventricular remodeling and are thus of central importance to understanding the pathophysiology of ischemic heart disease and its treatment.